DE3889302T2 - 9- (Acylamino) tetrahydroacridine derivatives and perceptual agents thereof as an active ingredient. - Google Patents

Description

The invention relates to a 9-acylamino-tetrahydroacridine derivative which is new and accessible and which improves the dysfunction of cholinergic neurons, its optical antipodes or pharmaceutically acceptable acid addition salt thereof and a memory-enhancing agent which contains these compounds as an active ingredient.

As a therapeutic method of various memory disorders characterized by a reduction in cholinergic nerve function, such as Alzheimer's disease, there is an attempt to increase the content of acetylcholine in the brain using an acetylcholine esterase inhibitor. For example, a study using physostigmine was reported in Neurology, Vol. 8, p. 377 (1978). Furthermore, in publications of Japanese Patent Provisional Publications No. 1481541/1986, No. 141980/1988, No. 166811/1988, No. 204664/1988, No. 225358/1988, No. 238063/1988 and No. 2392711/1988; EP-A-268 871; and International Provisional Patent Publication No. 88/02256 that specific 9-aminotetrahydroacridine derivatives have acetylcholine esterase inhibiting functions and are effective in the therapy of Alzheimer's disease. Also, it was reported by Summers in "The New England Journal of Medicine", vol. 315, p. 1241 (1986) that 9-amino-1,2,3,4-tetrahydroacridine (tacrine) is effective against Alzheimer's disease in humans in combination with the use of lecithin. However, the above methods have problems that sufficient improvement has not yet been achieved or that an adverse reaction is caused, so that a new therapeutic method has been desired.

On the other hand, as examples of the known 9-acylamino-tetrahydroacridine, 9-acetylamino-tetrahydroacridine are described in "Journal of Chemical Society", p. 634 (1947), and also 9-chloroacetylamino-tetrahydroacridine and 9-diethylaminoacetylamino-tetrahydroacridine are described in "Chem. Isty", vol. 51, p. 1056 (1957), where it is also mentioned that the latter has a local anesthetic effect. Furthermore, in "Journal of Medicinal Chemistry", Vol. 18, p. 1056 (1975), relationships regarding the structural activity of the acetylcholine esterase inhibiting function of 9-amino-tetrahydroacridine are described, whereby it is also described that the potencies of 9-acetylamino-tetrahydroacridine and 9-benzolyamino-tetrahydroacridine are 1/1000 of the of 9-amino-tetrahydroacridine. Furthermore, although 9-acylamino-tetrahydroacridine derivatives have been claimed in the above-mentioned patent publications (Japanese Provisional Patent Publications No. 166881/1988, No. 203664/1988, No. 225358/1988, No. 238063/1988 and No. 239271/1988), none of these publications have described concrete preparation examples or pharmacological activities of the compounds having a 9-acylamino group.

SUMMARY OF THE INVENTION

The present inventors have conducted extensive investigations to provide a therapeutic agent for senile dementia, including Alzheimer's disease, and as a result, they have found that a specific 9-acylamino-tetrahydroacridine derivative, its optical antipode or pharmaceutically acceptable acid addition salt thereof is an agent for improving memory impairment such as Alzheimer's disease, based on a different mechanism from that of the conventional compound having acetylcholine esterase inhibitory function, thereby completing the present invention.

That is, the present invention includes a compound of the following formula (I):

where:

R (i) a C₂₋₈-alkyl group, (ii) - (CH₂)n wherein n' = 1 to 3 or (iii) a group of formula (II):

wherein R¹ represents a hydrogen atom or a C₁₋₆ alkyl group, R² represents a hydrogen atom, where R³ is a hydrogen atom

or a C₁₋₆ alkyl group or

mean;

where in formula (II)

also can form

by combining R¹ and R² with each other; n is 1 or 2; wherein R⁴ represents a hydrogen atom, a halogen atom, a C₁₋₄ alkyl group, a C₁₋₄ alkoxy group or a hydroxyl group or

wherein R⁵ represents a hydrogen atom or a C₁₋₄alkyl group; and

wherein R⁶ represents a hydrogen atom, a C₁₋₄ alkyl group or

represents a hydroxyl group,

wherein R⁷ represents a hydrogen atom, a C₁₋₄ alkyl group, a benzyl group, a phenethyl group, (wherein R⁸ is hydrogen or an alkyl group),

wherein R⁹ represents a hydrogen atom or an alkyl group,

or

their optical antipode or a pharmaceutically acceptable acid addition salt thereof, as well as a memory-enhancing agent containing these compounds as an active ingredient.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

The present invention is explained in more detail below.

The 9-acylamino-tetrahydroacndin derivatives according to the invention are represented by the above formula (I).

In the formula (I), R means an alkyl group such as an alkyl group having 2 to 8 carbon atoms, preferably an alkyl group having 2 to 4 carbon atoms such as an ethyl group, n-propyl group, isopropyl group, n-butyl group, sec-butyl group and tert-butyl group; an aralkyl group such as

approximately

wherein n' = 1 to 3; or a group represented by the formula (II) .

In the formula (II), an alkyl group represented by R¹ and R³ may include an alkyl group having 1 to 6 carbon atoms, preferably an alkyl group having 1 to 4 carbon atoms, such as a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group and a sec-butyl group.

Also, in the formula (I), a halogen atom, an alkyl group, an alkoxy group or an aralkyl group represented by R⁴ to R⁷ may be mentioned as follows. The halogen atom may include a fluorine atom, a chlorine atom, a bromine atom or an iodine atom; the alkyl group may include an alkyl group having 1 to 4 carbon atoms such as a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, a sec-butyl group, etc.; the alkoxy group may include an alkoxy group having 1 to 4 carbon atoms such as a methoxy group, an ethoxy group, an n-propoxy group, an isopropoxy group, an n-butoxy group, a sec-butoxy group, etc.; and the aralkyl group may include a phenyl-C₁₋₃ alkyl group such as a benzyl group, a phenethyl group, etc.

Of the compounds represented by the formula (I), examples of the preferred substituents for the compound may include the following: (1) for pure n-propyl group, an isopropyl group or the compound represented by the formula (II). Particularly preferred are the compounds wherein R is the group of the formula (II) and

the meaning has n is 1.

(2) As , the compound in which

(3) As , the compound in which

Specific examples of the compound of the present invention are described in Table 1 and Table 2. Table 1 Compound No. R n Table 1 (continued) Compound No. R n Table 1 (continued) Compound No. R n taken together Table 1 (continued) Compound No. R n taken together Table 1 (continued) Connection No. R n taken together Table 1 (continued) Compound No. R n taken together Table 2 Compound No. R n taken together Table 2 (continued) Compound No. R n taken together Table 2 (continued) Compound No. R n taken together

Particularly preferred compounds of the present invention include Compound Nos. 2,3, 11, 19,20,23,26,28,30,32,34,37,39,41,44,45, 54, 61, 63, 64, 66 to 69, 72, 73, 77 to 80, 83, 84, 88, 89 and 92 to 94 in Tables 1 and 2 above.

As salts of the compounds represented by the formula (I), physiologically acceptable salts are preferred, and these may include an inorganic acid salt such as hydrochlorides, hydrobromides, hydroiodides, sulfates, phosphates, etc.; and an organic acid salt such as oxalates, maleates, fumarates, lactates, malates, citrates, tartrates, benzoates, methanesulfonates, etc. Since the compounds of the formula (I) or salts thereof may be in the form of hydrates or solvates, the hydrates and solvates thereof are also included in the compounds of the present invention.

The process for preparing the compounds according to the invention is described below.

The compounds of the invention can be prepared, for example, by any of the following processes.

(1) By reacting the compound of formula (III):

wherein and have the same meanings as defined in the above formula (I), with a reactive derivative of the compound represented by the formula (IV):

wherein R¹⁰ represents an alkyl group or aralkyl group as represented by R in the formula (I),

the compound of formula (I) can be obtained.

Examples of the reactive derivatives of the compound of formula (IV) are preferably symmetrical acid anhydrides or acid halides (particularly acid chloride). The reaction is carried out in the presence of an inert solvent such as benzene, toluene, xylene, 1,2-dichloroethane, 1,1,2,2-tetrachloroethane, etc., or by using excess amounts of symmetrical acid anhydrides or acid halides as solvents. When the symmetrical When acid anhydrides are used, a tertiary amine such as pyridine may be used. The reaction is carried out at a temperature in the range of 30 to 150°C, preferably 50 to 120°C.

(2) After further treating the compound of the above formula (111) with an equimolar amount or more of sodium hydride to produce a sodium salt, this is reacted with an ester compound of the formula (V):

implemented,

where R¹¹ has the meaning

and R¹² represents a methyl group or ethyl group, to obtain the compound represented by the formula (I).

Tetrahydrofuran, dioxane, acetonitrile, dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, etc. are preferred as solvents. The reaction is carried out at a temperature in the range of 10 to 80°C, preferably 30 to 60°C.

x

wherein X represents a chlorine atom or a bromine atom; m represents 1 or 2; and have the same meanings as in formula (I) defined; R¹³ in formula (VIII) represents a straight- or branched-chain alkyl group having 1 to 6 carbon atoms; or

represents an alkyl group having 1 to 4 carbon atoms); R¹⁴ in the formula (IX) represents

Using the above two steps of the reaction equation, the compound of formula (I) can be synthesized.

That is, an acyl halide compound of formula (VI) is reacted with the compound of formula (III) to obtain the compound of formula (VII) [step (a)]. Then, the compound of formula (VII) is reacted with the compound of formula (VIII) or imidazole or with a compound which is a sodium salt obtained by treating the compound of formula (IX) with sodium hydride [step (b)], whereby the corresponding compound (I) can be obtained.

The step (a) is carried out using an excess amount of acyl halide as well as a solvent or using an inert solvent such as benzene, toluene, xylene, 1,2-dichloroethane, 1,1,2,2-tetrachloroethane, etc. at a temperature in the range of 50 to 150°C, preferably 70 to 120°C.

The step (b) is carried out using an excess amount of amine as a solvent or using an alcoholic solvent such as methanol, ethanol, n-propanol, isopropanol, n-butanol, etc., or a solvent such as tetrahydrofuran, dioxane, acetonitrile, dimethylformamide, dimethyl sulfoxide, etc. at a temperature in the range of 0 to 150°C, preferably 20 to 100°C. When the sodium salt of the compound of formula (X) is reacted, the reaction is carried out using a solvent such as tetrahydrofuran, dioxane, acetonitrile, dimethylformamide, dimethyl sulfoxide, etc. at a temperature in the range of 0 to 120ºC, preferably 20 to 80ºC.

where X, m, and have the meanings defined above.

By using the above compound of formula (VII), the compound of formula (I) can be obtained by the above reactions in three steps.

That is, sodium azide is reacted with the compound of formula (VII) [step (c)] to obtain the azide compound of formula (X), the compound is reduced [step (d)] by the method of hydrogenolysis using, for example, palladium as a catalyst to obtain a primary amine compound of formula (XI), and then this compound is subjected to acylation [step (e)] or carbamoylation [step (f)] to obtain the compound of formula (I).

The step (c) is carried out in a solvent such as dimethylformamide, dimethyl sulfoxide, acetonitrile, methanol, ethanol, n-propanol, isopropanol, etc., or in a mixed solvent of the above solvents and water at a temperature in the range of 0 to 80°C, preferably 10 to 50°C.

Step (d) is carried out in a solvent such as methanol, ethanol, n-propanol, isopropanol, tetrahydrofuran, dioxane, acetonitrile, etc., at a temperature in the range of 0 to 80ºC, preferably 10 to 40ºC.

Step (e) is carried out under the usual acylation conditions, for example in the presence of a tertiary amine, by reaction with an acyl halide compound or a symmetrical acid anhydride.

Step (f) can be carried out under the conditions of conventional carbamoylation. For example, when the compound of formula (XI) is reacted with alkyl isocyanate, an alkyl-substituted urea can be obtained, and when it is reacted with sodium isocyanate in acetic acid, a urea derivative can be obtained.

(5) As a method for converting a compound of formula (I) into the other compound encompassed by formula (I), the following methods can be used.

wherein R and in formulas (XII) and (XIII) have the same meanings as defined in formula (I) above.

That is, N-benzylamine as represented by formula (XII) is subjected to debenzylation by hydrogenolysis using palladium as a catalyst [step (g)I, after which the obtained secondary amine of formula (XIII) is subjected to acylation [step (h)] or carbamoylation [step (i)].

The step (g) can be carried out by the usual method, for example, hydrogenolysis is carried out by using palladium-carbon as a catalyst and by adding hydrochloric acid. The steps (h) and (i) can be carried out by the same methods of the above steps (e) and (f) in the above paragraph (4).

The compound of formula (III), which is the starting material of the preparation processes according to (1) to (3), can be synthesized in a simple manner, for example by the method described in (a) Tetrahedron Letters, p. 1277 (1963); (b) Collection of Czechoslovak Chemical Communications, Vol. 42, p. 2802 (1977); (c) Acta Chemica Scandinavica, B, Vol. 33, p. 313 (1979); etc. or corresponding methods.

Also, it can be synthesized in the manner described in each of Japanese Patent Provisional Publications No. 148154/1986, No. 141980/1988, No. 166881/1988, No. 203664/1988, No. 225358/1988, No. 238063/1988 and No. 239271/1988; and EP-A-268 871.

When the compound of the invention is used as a therapeutic agent, it may be administered singly or as a composite by mixing with a pharmaceutically acceptable carrier. Compositions therefor may be determined by the solubility, chemical properties, route of administration, administration schedule, etc. of the compounds.

For example, it can be administered orally in the form of granules, fine granules, powders, tablets, hard capsules, soft capsules, syrups, emulsions, suspensions or liquids, or intravenously, intramuscularly or subcutaneously as an injection.

Also, it can be used by preparing a powder for injection in the manner that they are prepared in use. An organic or inorganic carrier which is in the form of a solid or a liquid or a diluent which are pharmaceutically acceptable for oral, rectal, parenteral or local administration can be used in combination with the compound of the invention. As excipients for use in preparing solid preparations, for example, lactose, sugar, starch, talc, cellulose, dextrin, kaolin, calcium carbonate, etc. are used. Liquid preparations for oral administration, i.e. Emulsions, syrups, suspensions, liquids, etc., contain inert diluents which are conventionally used, such as water or vegetable oils, etc. These preparations may contain, in addition to the inert diluents, excipients, for example wetting agents, suspension aids, sweeteners, flavourings, colouring agents or preservatives, etc. They may be prepared in the form of liquid preparations and contained in a capsule made of a substance which is absorbable, such as gelatin, etc. As preparations for parenteral administration, i.e. solvents or suspending agents to be used for the preparation of injections, etc., there may be mentioned, for example, water, propylene glycol, polyethylene glycol, benzyl alcohol, ethyl oleate, lecithin, etc. The manufacturing processes for the preparations may be based on conventional processes.

As for the clinical dose, when used by oral administration, a daily dose of the compound of the invention is generally 1 to 1000 mg, preferably 1 to 100 mg, for an adult, but the dose may optionally be varied depending on the age, severity of the disease, condition of the patient, presence or absence of concurrent administration, etc. The above daily dose of the compound of the invention may be administered once a day or two to three times a day at appropriate intervals by dividing it, or it may be administered intermittently.

When used in the form of injections, it is used in a daily dose of 0.1 to 100 mg, preferably 0.1 to 50 mg, based on the compound of the invention in an adult.

Although the thus prepared compound of the present invention of formula (I) is weak in acetylcholine esterase inhibiting ability, such as about 1/100 or less as compared with the known 9-amino-tetrahydroacridine, neurotransmission can be increased by activating a presynaptic site of cholinergic neurons. In particular, high-affinity choline uptake in the hippocampal synaptosome of the AF64A-injected rat (ethylcholine-aziridine luminon) [Journal of Pharmacology and Experimental Therapeutics, vol. 222, p. 140 (1982); Neuropharmacology, vol. 26, p. 361 (1987)] can be improved in brain ventricles (see Test Example 1). This activation could not be found with 9-amino-tetrahydroacridine.

The compound of the invention is also extremely weak in toxicity and shows only minor adverse reactions compared to 9-amino-tetrahydroacridine so that it can be provided as a therapeutic agent against memory disorders such as Alzheimer's disease, etc.

The compound of formula (I) according to the invention is a physiologically active and valuable compound. In particular, these compounds have the function of directly activating a depressed cholinergic nervous system, so that they are available as drugs which are suitable for the therapy of memory disorders such as Alzheimer's disease.

In dementia, especially Alzheimer's disease, the functions of cholinergic neurons in the brain are reduced, and there is a good correlation between this reduction and the degree of memory impairment. On the other hand, AF64A reduces cholinergic neurons selectively and over a longer period of time, as reported by Fisher [Journal of Pharmacology and Experimental Therapeutics, Vol. 222, p. 140 (1982)] and Leventer [Neuropharmacology. Vol. 26, p. 361 and studies are being carried out [Brain Research, Vol. 321, p. 91 (1984)], so that this is a good model for Alzheimer's disease. Accordingly, the compounds of the invention, which can directly activate the function of cholinergic neurons in the brain, which is reduced by injection with AF64A, can be considered available for the therapy of senile dementia, including Alzheimer's disease.

EXAMPLES

The invention is explained in more detail below.

example 1 Synthesis of N-(1,2,3,4-tetrahydroacridin-9-yl)-butanamide (Compound No. 2 in Table 1)

To 4 ml of pyridine was added 2 g of 9-amino-1,2,3,4-tetrahydroacridine. To the mixture was added 3.3 ml of n-butyric anhydride and the mixture was refluxed for 8 hours. Then, the solvent was removed under reduced pressure and to the resulting residue was added 10 ml of methanol. To the mixture was added concentrated aqueous ammonia and the mixture was refluxed for one hour. After removing the solvent under reduced pressure, water was added to the residue and the mixture was extracted with chloroform. The chloroform layer was dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure. The resulting residue was purified by silica gel column chromatography and recrystallized from chloroform/ether to obtain 1.57 g of N-(1,2,3,4-tetrahydroacridin-9-yl)butanamide. Melting point 220 to 204ºC.

In the same manner as in Example 1, the compounds shown in Table 3 were synthesized.

Reference example 1

In the same manner as in Example 1, the compound of Reference Example 1 was synthesized as shown in Table 3. Table 3 Example No. R Melting point Hydrochloride decomposes Dihydrochloride Reference example Amorphous solid

Example 14 Synthesis of 2-(2-oxopyrrolidin-1-yl)-N-(1,2,3,4-tetrahydroacridln-9-yl)acetamide hydrochloride (compound no. 26 in Table 1)

In 50 ml of N-methylpyrrollidone, 4.4 g (content: 60%) of sodium hydride was suspended, then 10.4 g of 9-amino-1,2,3,4-tetrahydroacridine was added to the suspension and the mixture was stirred at room temperature for one hour. Then, the reaction system was raised to 50°C and 17.4 g of methyl 2-oxo-1-pyrrolidine acetate was added dropwise to the mixture over 30 minutes. After cooling to 10°C, the mixture was poured into 300 ml of an aqueous solution containing 40 g of ammonium chloride and extracted with 300 ml of chloroform. The chloroform solution was evaporated to dryness and recrystallized from isopropanol to obtain 14.9 g of crystals. Melting point: 233 to 236°C. These crystals were suspended in 120 mL of isopropanol, then 10 mL of a 26% hydrogen chloride-isopropanol solution was added. After stirring the mixture at room temperature for 1 hour, it was filtered to obtain 15.2 g of the title compound. Melting point: 230-235°C (dec.).

In the same manner as in Example 14, the compounds shown in Table 4 below were synthesized. Table 4 Example No. Melting point Dihydrochloride Maleate Table 4 (continued) Example No. Melting point Amorphous solid Maleate

Example 34 Synthesis of 2-(2,4-imidazolidinedion-3-yl)-N-(1,2,3,4-tetrahydroacridin- 9-yl)-acetamide (compound no. 37 of Table 1)

In 20 ml of dimethylformamide was suspended 0.8 g (content: 60%) of sodium hydride, then 3 g of 2,4-imidazolidinedione was added to the suspension and the mixture was stirred at room temperature for 30 minutes. Then 2.75 g of 9-chloroacetylamino-1,2,3,4-tetrahydroacridine (described in "Chem. listy", vol. 51, p. 1906 (1957)) was added to the mixture and a reaction was carried out by heating at 80°C for 30 minutes. After cooling to 10°C, the mixture was poured into 100 ml of an aqueous solution containing 8 g of ammonium chloride. The precipitated crystals were collected by filtration, washed with water and dried. These crystals were recrystallized from methanol-chloroform to give 2.5 g of the title compound. M.P.: 302-304°C (dec.).

In the same manner as in Example 34, the compounds shown in Table 5 below were synthesized. Table 5 Example No. Melting point decomposed

Example 39 Synthesis of 9-[(2-methylamino)-acetylaminol-1,2,3,4-tetrahydroacridine (Compound No. 11 in Table 1)

To 30 ml of a 40% methylamine-methanol solution was added 1.4 g of 9-chloroacetylamino-1,2,3,4-tetrahydroacridine, and the mixture was reacted at room temperature for 2 hours and then at 50°C for 30 minutes. Then, the mixture was extracted by adding 60 ml of water and 80 ml of chloroform. The chloroform solution was condensed and purified by silica gel column chromatography (chloroform-methanol), and recrystallization from isopropanol-diethyl ether gave 0.89 g of the title compound. Melting point 152-155°C.

In the same manner as in Example 39, the compounds of Examples 40 and 41 were synthesized. The compound of Example 39 was also subjected to acetylation with acetic anhydride-pyridine in a conventional manner to prepare the compound of the following Example 42. The melting points of these compounds are shown in Table 6. Table 6 Example No. Melting point

Example 43 Synthesis of 9-[(2-amino)-acetylamino]-1,2,3,4-tetrahydroacridine (Compound No. 10 in Table 1)

In 40 ml of dimethylformamide was suspended 2.84 g of sodium azide, then 10 g of 9-chloroacetylamino-1,2,3,4-tetrahydroacridine was added and the mixture was reacted at room temperature for 2 hours. After adding 32 ml of water to the mixture, the precipitated crystals were filtered to obtain 9.7 g of 9-azidoacetylamino-1,2,3,4-tetrahydroacridine. Melting point: 190°C (decomposed). These crystals were suspended in 500 ml of methanol, and hydrogenolysis was carried out by adding 0.5 g of palladium black at room temperature for 1 hour. After removing the catalyst by filtration, the filtrate was condensed and recrystallized from methanol-isopropanol and then filtered to obtain 7.4 g of the title compound. Melting point: 225 to 230ºC.

The compound of Example 43 was subjected to acylation or carbamoylation in a conventional manner to produce the compounds shown in Table 7 below. Table 7 Example No. Melting point decomposed

Example 48 Synthesis of 2-(2-oxopyrrolidin-1-yl)-N-(1,2,3,4-tetrahydrobenzo[b]- [1,6]naphthylidin-10-yl)-acetamide maleate (1 : 1) (compound no. 67 in Table 2)

In a mixed solvent of 200 ml of ethanol and 100 ml of acetic acid, 10.2 g of the free base of the compound of Example 21 was dissolved, and hydrogenolysis was carried out by adding 6 ml of a 30% hydrogen chloride-ethanol solution and 1.5 g of a 5% palladium-carbon solution at atmospheric pressure and 50°C for 6 hours. After removing the catalyst by filtration, the solvent was evaporated to dryness and the remaining solid was recrystallized from ethanol to obtain 8.7 g of crude crystals. These crystals were added to 100 ml of a saturated aqueous sodium hydrogen carbonate solution and 150 ml of chloroform and the mixture was stirred. After drying the chloroform solution over sodium sulfate, the chloroform was removed and the residue was dissolved in 60 ml of methanol. Then, 60 ml of a methanol solution containing 2.6 g of maleic acid was added to the solution and the precipitated crystals were collected by filtration to obtain 7.5 g of the title compound. Melting point: 192 to 198°C (decomposed).

The free base of the compound of Example 48 was subjected to acylation or carbamoylation in a conventional manner to produce the compounds shown in Table 8 below. Table 8 Example No. Melting point decomposed maleate

Example 52 Synthesis of N-(3,4-dihydroacridin-2(1H)on-9-yl)-butanamide (Compound No. 76 in Table 2)

In 30 ml of acetone was dissolved 3.6 g of the compound of Reference Example 1, and by adding 7 ml of 2N hydrochloric acid, the reaction was carried out at 50°C for 3 hours. The solvent was removed under reduced pressure, to the residue were added 100 ml of chloroform and 30 ml of a 10% aqueous solution of potassium carbonate, and the mixture was stirred. The chloroform layer was separated, dried over sodium sulfate, condensed and crystallized from chloroform-diethyl ether to obtain 2.4 g of the title compound. Melting point: 213-217°C (decomposed).

Example 53 Synthesis of N-(1,2,3,4-tetrahydroacridin-2-ol-9-yl)-butanamide (Compound No. 8 in Table 1)

In 20 ml of methanol was dissolved 1 g of the compound of Example 52, 0.14 g of sodium borohydride was added to the solution and a reaction was carried out at room temperature for 12 hours. After removing the solvent under reduced pressure, 30 ml of chloroform and 30 ml of water were added to the residue and the mixture was stirred. The chloroform layer was separated, dried over sodium sulfate and then condensed and crystallized from chloroform-ethyl acetate to obtain 0.77 g of the title compound. Melting point: 260 to 265°C (dec.).

Reference example 2 Synthesis of 4-amino-5,6,7,8-tetrahydro-thieno[2,3-b]quinoline

To 45 ml of cyclohexanone were added 7.54 g of zinc chloride and 5.56 g of 2-amino-3-cyanothiophene, and a reaction was carried out at 100 to 110°C for 2 hours. After cooling the reaction system to 20°C, 20 ml of ethyl acetate was added and crystals were filtered off. These crystals were suspended in 100 ml of chloroform, and the suspension was stirred by adding 17 ml of concentrated aqueous ammonia. The chloroform solution was dried over sodium sulfate, condensed and crystallized from chloroform-n-heptane to obtain 6.11 g of the title compound. Melting point: 159 to 161°C.

Reference example 3 Synthesis of 10-amino-1H-3,4-dihydro-pyrano[4,3-b]quinoline

5.04 g of tetrahydro-4H-pyran-4-one and 8.92 g of zinc chloride were mixed with 5.95 g of 2-aminobenzonitrile and the mixture was reacted at 90ºC for one hour. After cooling to room temperature, the resulting solid was crushed by adding 20 ml of toluene and filtered. This Solid was suspended in 180 ml of chloroform and the suspension was stirred with addition of 22 ml of concentrated aqueous ammonia. The chloroform solution was separated therefrom, dried over sodium sulfate, condensed and crystallized from chloroform-n-heptane to give 5.84 g of the title compound. Melting point: 199-202°C.

Reference example 4 Synthesis of 4-amino-5H-7,8-dihydro-pyrano[4,3-b]thieno[3,2-e]pyridine

The title compound was synthesized in the same manner as in Reference Example 3. Melting point: 199-202ºC.

Reference example 5 Synthesis of 10-amino-2-benzyl-1,2,3,4-tetrahydro-benzo[b][1,6]naphthylidine

To 400 ml of dimethylformamide were added 55 g of isatin, 76.2 g N-benzyl-4-piperidone and 86.4 g of ammonium acetate and the reaction was carried out at 120°C for 3 hours. After removing the solvent under reduced pressure, 200 ml of acetone and 200 ml of water were added to the residue and insolubles were collected by filtration. These insolubles were suspended in 400 ml of ethanol and washed and then filtered to obtain 67.8 g of 2-benzyl-10-carbamoyl-1,2,3,4-tetrahydro-benzo[b][1,6]naphthylidine. Melting point: 234 to 237°C.

In 250 ml of water, 20.2 g of sodium hydroxide was dissolved, 22.2 g of bromine was added dropwise at -5°C, followed by 40 g of carboxamide of the above compound, and the mixture was raised to 80°C for 4 hours with thorough stirring. After cooling the mixture to 20°C, precipitated crystals were collected by filtration, washed and recrystallized from methanol to obtain 13 g of the title compound. Melting point: 193-196°C.

Reference example 6 Synthesis of 10-amino-2-methyl-1,2,3,4-tetrahydro-benzo[b][1,6]naphthylidine

In the same manner as in Reference Example 5, the title compound was synthesized. Melting point: 169-171ºC.

Reference example 7 Synthesis of 10-amino-2-methyl-1,3-propane-1,2,3,4-tetrahydro-benzo- [b][1,6]naphthylidine

4.36 g of 2-aminobenzonitrile and 7 g of pseudopelletierin hydrochloride were mixed with 5.53 g of zinc chloride and the mixture was reacted at 150ºC for 2.5 hours. After cooling to room temperature, the resulting solid was crushed by adding 10 ml of isopropanol and filtered. This Solid was suspended in 100 ml of chloroform and the suspension was stirred with addition of 22 ml of concentrated aqueous ammonia. The chloroform solution was separated therefrom, condensed, purified by silica gel column chromatography (chloroform-methanol) and recrystallized from ethyl acetate to give 1.2 g of the title compound. Melting point: 220-240°C (dec.).

Reference example 8 Synthesis of 4-amino-5,8-ethane-5,6,7,8-tetrahydro-thieno[2,3-b][1,5]naphthylidine

5 g of 2-amino-3-cyanothiophene and 3-quinucridinone hydrochloride were mixed with 6.04 g of zinc chloride and the mixture was reacted at 110°C for 1 hour. After cooling to room temperature, the resulting solid was crushed by adding 100 ml of chloroform, then 30 ml of concentrated aqueous ammonia and 10 ml of methanol were added and the mixture was stirred. Insoluble matter was removed by filtration and the chloroform layer was separated therefrom, condensed, purified by silica gel column chromatography and recrystallized from ethyl acetate to obtain 0.59 g of the title compound. Melting point: 265 to 268°C (dec.).

Test example 1

Effects on Na+-dependent high-affinity choline uptake (HACU) of the hippocampus of the AF64A-treated rat

(Procedure)

AF64A was prepared from AF64 according to the method of Fischer et al. [J. Pharm. Exper. Ther., vol. 222, p. 140 (1982)]. AF64A (1.5 nmol/1.5 μl/side) was injected into both ventricles of the rat. After one week, after the head was removed, only the hippocampus was taken. It was homogenized with 0.32M sucrose, centrifuged at 1000 g for 10 minutes, and the supernatant was further centrifuged at 20,000 g for 20 minutes to obtain a crude synaptosomal fraction. The crude synaptosomal fraction and the drug were incubated at 37°C for 30 minutes, and after addition of [3H]-Cholln (1 μM), they were further incubated at 37°C for 10 minutes.

As a control, the crude synaptosomal fraction was subjected to incubation at 37ºC for 30 minutes and, after addition of [³H]-choline (1 µM), to a further incubation at 37ºC for 10 minutes. The reaction was stopped by filtration on a Whatman GF/B filter. The radioactivity on the filter was measured using a liquid scintillation counter and taken as the amount of HACU. The amount of protein was according to the method of Bradford [Analytical Chemistry, Vol. 72, p. 248 (1976)]. The test results are shown in Table 9. Table 9 Improvement ratio (% relative to control) Example No. Compares

Compare: 9-amino-1,2,3,4-tetrahydroacridine

Test example 2 Acute toxicity testing

The compound of the present invention was orally administered to a mouse and the acute toxicity value was measured. The results are shown in Table 10. Table 10 Example No. of compound Acute toxicity value (LD₅₀ mg/kg) 9-Amino-1,2,3,4-tetrahydroacridine

Claims (9)

1. A compound of the following formula (I): where: R (i) a C₂₋₈-alkyl group, (ii) where n = 1 to 3 or (iii) a group of formula (II): wherein R¹ represents a hydrogen atom or a C₁₋₆ alkyl group, R² represents a hydrogen atom, wherein R³ represents a hydrogen atom or a C₁₋₆ alkyl group or or R¹ and R² together with the nitrogen atom to which they are attached form and n is 1 or 2; A (i) wherein R⁴ is hydrogen, halogen, C₁₋₄-alkyl, C₁₋₄-alkoxy or hydroxyl; or (iii) wherein R⁵ is hydrogen or C₁₋₄alkyl; and wherein R⁶ is hydrogen, C₁₋₄-alkyl or hydroxyl, wherein R⁷ is hydrogen, C₁₋₄-alkyl, benzyl, phenethyl, wherein R⁸ is hydrogen or an alkyl group means, wherein R⁹ represents a hydrogen atom or an alkyl group, its optical antipode or a pharmaceutically acceptable acid addition salt thereof. 2. A compound according to claim 1, wherein R is the group (iii) represented by formula (II). 3. A compound according to claim 1, wherein the alkyl group of the substituent R is ethyl, n-propyl, isopropyl, n-butyl, sec-butyl or t-butyl. 4. A compound according to claim 1, wherein the alkyl group of the substituents R¹ and R² is methyl, ethyl, n-propyl, isopropyl, n-butyl or sec-butyl. 5. A compound according to claim 1, wherein in the groups R⁴ to R⁷ the halogen is fluorine, chlorine, bromine or iodine, the alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl or sec-butyl and the alkoxy group is methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy or sec-butoxy. 6. A compound according to claim 1, wherein the -Groups in the formula (11) of the substituent R are; and n is 1. 7. A compound according to claim 1, wherein the ring has the meaning 8. A compound according to claim 1, wherein the ring has the meaning 9. Pharmaceutical composition for increasing memory or the ability to remember, characterized in that the composition contains a pharmaceutically effective amount of a 9-acylamino-tetrahydroacridine derivative, an optical antipode or a pharmaceutically acceptable acid addition salt thereof according to claim 1 in combination with a pharmaceutically acceptable carrier.